No Association of Antenatal Synthetic Glucocorticoid Exposure and Hair Steroid Levels in Children and Adolescents.

CONTEXT: Antenatal synthetic glucocorticoid (sGC) treatment constitutes a potent programming factor of the hypothalamic-pituitary-adrenal (HPA) axis. Previous findings from our group revealed long-term changes in cortisol stress reactivity following antenatal sGC therapy. However, the few prior studies exclusively relied on spot measurements of phasic HPA axis activity, which may not adequately capture cortisol output over prolonged periods of time. OBJECTIVE: To address this gap, the current study utilized hair steroid concentrations, a valid marker of integrated long-term HPA-axis activity, to investigate endocrine changes in individuals treated with antenatal sGC. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study comprised 76 term-born children (7-12 years) and 58 adolescents (14-18 years). Cumulated hormonal secretion in scalp hair over a 3-month period was determined for different biomarkers of tonic HPA axis activity by liquid chromatography coupled with tandem mass spectrometry. Hair steroid levels were compared between participants with antenatal sGC therapy (dexamethasone or betamethasone) and different control groups. RESULTS: Findings from this study provide no evidence for a significant effect of antenatal sGCs on long-term hair steroid concentrations. Participants treated with antenatal sGC exhibited comparable levels of hair cortisol, cortisone, dehydroepiandrosterone, and cortisol/dehydroepiandrosterone ratios compared to those of mothers who had been admitted to hospital for pregnancy complications but had never received sGC therapy and controls from physiological pregnancies. CONCLUSION: In conjunction with data from previous studies, it is thus tempting to speculate that sGC may affect the capacity of dynamic changes and flexible adaption of an individual's HPA axis rather than changes in tonic steroid output.

Persistent Effects of Antenatal Synthetic Glucocorticoids on Endocrine Stress Reactivity From Childhood to Adolescence.

Context: Antenatal synthetic glucocorticoid (sGC) therapy has been identified as a potent programming factor of the hypothalamic-pituitary-adrenal (HPA) axis. We previously observed significantly increased cortisol stress responses in 6- to 11-year-old, term-born children exposed to antenatal sGCs compared with controls. These findings call for longitudinal follow-up studies to evaluate long-term effects of antenatal sGCs, given that adolescence is marked by a substantial shift of HPA axis functioning. Objective: This study aimed to longitudinally investigate the stability of antenatal sGC-related effects on cortisol stress reactivity from childhood to adolescence. Design, Setting, and Participants: To evaluate long-term trajectories of antenatal sGCs, we longitudinally followed a subsample (n = 44) of our children's cohort into adolescence (14 to 18 years old) for a second assessment. To this end, 22 adolescents with antenatal sGC exposure and 22 untreated controls underwent a standardized laboratory stressor [Trier Social Stress Test (TSST)]. Results: Besides a general increase in HPA axis reactivity from childhood to adolescence (P < 0.05), participants treated with antenatal sGCs showed significantly higher cortisol levels in response to the TSST compared with controls during both developmental stages (P < 0.05). Furthermore, we observed a moderating effect of sGCs on rank-order stability of cortisol stress reactivity from childhood to adolescence (P < 0.05) with a trend (P = 0.07) for higher rank-order stability in sGC-exposed individuals (r = 0.37) compared with controls (r = -0.20). Conclusion: These findings suggest that antenatal sGCs yield long-term changes of HPA axis reactivity that persist into adolescence and may confer increased vulnerability for developing stress-related disorders.

Impact of Antenatal Glucocorticoid Therapy and Risk of Preterm Delivery on Intelligence in Term-Born Children.

CONTEXT: Women at risk of preterm delivery are routinely treated with synthetic glucocorticoids (sGCs). Although this therapy substantially reduces neonatal morbidity, concerns remain whether sGC excess may disrupt neurodevelopmental trajectories underlying cognitive functioning. OBJECTIVE: The present study is the first to disentangle direct effects of antenatal sGC treatment on possible long-term cognitive disadvantages from those of pregnancy complications and prematurity. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included a mixed-sex cohort of 222 term-born children (aged 6-11 years) consisting of three groups: children of mothers admitted to hospital for threatening preterm delivery who had been treated (n = 97) or untreated (n = 36) with sGCs, and controls without pregnancy complications (n = 89). INTERVENTION: Antenatal sGC treatment consisted of single courses with dexamethasone or betamethasone. MAIN OUTCOME MEASURE: Psychometric intelligence was assessed using a German adaption of Cattell's Culture Fair Test. RESULTS: Children born to mothers at risk for preterm delivery scored, on average, 6-7 IQ points below children of mothers without pregnancy complications, irrespective of antenatal sGC treatment. Compared to females, boys were found to be more susceptible to cognitive disadvantages associated with maternal risk for preterm delivery. CONCLUSIONS: Our data indicate that conditions related to a threatening preterm delivery rather than antenatal sGC treatment per se are associated with long-term decreases in the child's intelligence. Although these findings imply that a single course of sGC therapy does not aggravate long-term cognitive deficits, they highlight the need for interventions to reduce the detrimental consequences of distress induced by a threatening preterm delivery.

Impact of antenatal synthetic glucocorticoid exposure on endocrine stress reactivity in term-born children.

CONTEXT: Antenatal glucocorticoid (GC) exposure has been discussed as a potent programming factor of hypothalamus-pituitary-adrenal (HPA) axis activity, producing sustained alterations in cortisol secretion throughout life. So far, the assessment of HPA-axis activity in offspring of mothers treated with synthetic GC has been limited to a time period shortly after birth, with prematurity being an important confound in most prior studies. OBJECTIVE: The present study aimed to investigate HPA-axis reactivity of term-born children with antenatal GC exposure in a larger sample, allowing us to further address sex- and drug-specific effects. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study comprised of 209 term-born children between 6 and 11 yr of age. Cortisol secretion patterns in response to a standardized laboratory stressor (Trier Social Stress Test for Children) were assessed in children with antenatal GC exposure (a single course of either dexamethasone or betamethasone) and compared to different control groups. RESULTS: We observed significantly increased cortisol reactivity to acute psychosocial stress in 6- to 11-yr-old, term-born children exposed to antenatal synthetic GC treatment compared to controls (F(3.4,345.9)=5.8; P<0.001). This finding appeared to be independent of the specific synthetic GC used and was found to be more pronounced in females. CONCLUSIONS: The present study provides the first evidence for long-lasting effects of antenatal synthetic GC exposure on HPA-axis reactivity in term-born children. These findings may bear important implications regarding the vulnerability for stress-related physical and psychiatric disorders, for which dysregulation of the HPA-axis has been discussed as a potential causal factor.